Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of L-DOPA-induced dyskinesia.
Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT(1A) and 5-HT(1B) agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT(1) agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.
Muñoz
Ana
A
Department of Experimental Medical Science, Neurobiology Unit, Wallenberg Neuroscience Center, University of Lund, Lund, Sweden.
Li
Qin
Q
Gardoni
Fabrizio
F
Marcello
Elena
E
Qin
Chuan
C
Carlsson
Thomas
T
Kirik
Deniz
D
Di Luca
Monica
M
Björklund
Anders
A
Bezard
Erwan
E
Carta
Manolo
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000978:Antiparkinson Agents; C097067:CP 94253; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D007980:Levodopa; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine